Current Research

Epigenetic mechanisms in brain development and neurodevelopmental diseases

Epigenetic modifications play an important role in regulating chromatin dynamics and therefore have a significant impact on gene expression. My research utilizes biochemistry, bioinformatics, cell-based analysis, and animal models to study the function of chromatin modifying enzymes and covalent histone modifications in regulating gene expression in normal development and diseases. Specifically, the study in my lab focuses on the epigenetic mechanisms in transcriptional regulation and its functions in neurodevelopmental diseases. We have established two new ASD mouse models by genetic deletion of ASD risk genes Ash1l and Kdm6b. Using these two mouse models, we demonstrate that loss of Ash1l or Kdm6b is sufficient to induce ASD-like behavioral deficits, confirming that disruptive ASH1L or KDM6B mutations are likely to be the causative drivers leading to ASD genesis in human patients. Moreover, we demonstrate that neural hyperactivity is a core pathophysiological change in the Ash1l-deficient mouse brain, revealing that excitation/inhibition imbalance is a key change leading to the ASD-like behavioral deficits in the Ash1-deficient mice. Based on our biochemical findings that the synergistic effect of ASH1L-mediated histone H3K36me2 and CBP-mediated histone acetylation in transcriptional activation, we further demonstrated that administration of histone deacetylase inhibitor largely ameliorates the behavioral and cognitive deficits in Ash1l-deficient mice, providing a potential new pharmacological treatment for the ASH1L-mutation-induced ASD. In addition, my lab discovers that histone demethylase KDM2B is critical for maintaining the neural stem cell population in the developing mouse brain and revealed its pathogenic role and epigenetic mechanisms in the chromosomal 12q24.31-deletion-associated ASD genesis. The long-term goal of my research is to utilize the molecular mechanisms revealed by our studies to develop effective epigenetics-based therapies to treat autism and other neurodevelopmental diseases.